PTP1B: a double agent in metabolism and oncogenesis

Abstract

PTP1B, a non-transmembrane protein tyrosine phosphatase that has long been studied as a negative regulator of insulin and leptin signaling, has recently received renewed attention as an unexpected positive factor in tumorigenesis. In this review, we highlight how views of this enzyme have evolved from regarding it as a simple metabolic off-switch to a more complex view of PTP1B as an enzyme that can play both negative and positive roles diverse signaling pathways. These dual characteristics make PTP1B a particularly attractive therapeutic target for diabetes, obesity, and perhaps breast cancer. PTP1B: signaling paradigm and paradoxImagine a pill that could keep you thin, free of diabetes, and protected from breast cancer. This hypothetical medicine would need to have the seemingly magical property of stimulating pathways that signal weight loss and lower blood sugar while simultaneously blocking those that induce cell proliferation and cell survival. In the enzyme protein tyrosine phosphatase 1B (PTP1B), a target for such a hypothetical drug exists. This review is not about how to make such a drug (although many are trying); instead it discusses the unusual combination of properties that render PTP1B such an attractive drug target for a variety of common and serious diseases.PTP1B was the first enzyme of its class to be purified to homogeneity [1,2] and, with its close cousin TC-PTP, the first to be intentionally cloned [3][4][5]. Many of the seminal concepts regarding PTP regulation, structure, and function were first discovered in the context of PTP1B. As such, PTP1B can be viewed as a touchstone in phosphatase research, the reference enzyme to which other PTPs are most often compared, much as Src serves as a paradigm for cytoplasmic protein tyrosine kinases. Despite its emblematic role as the prototypical PTP, PTP1B has a number of unique properties that clearly distinguish it from other enzymes in its class, and important new discoveries regarding PTP1B continue to be made with surprising regularity (Table 1).

SENP1 regulates IFN-γ−STAT1 signaling through STAT3−SOCS3 negative feedback loop

“…Therefore, our studies support the proposal that the function of SENP1 as a positive regulator in STAT1-induced macrophage activation is mainly through de-SUMOylation of PTP1B, which reduces inhibition of STAT3−SOCS3 on STAT1 signaling. PTP1B engagement is well known for the regulation of insulin-stimulating signaling (Yip et al, 2010). Our study shows that PTP1B is also essential for IFNγ-induced macrophage activation.…”

High-resolution dose–response screening using droplet-based microfluidics

“…S10 and SI Text). Table S3) was then screened for inhibition of PTP1B, a target for type 2 diabetes mellitus, obesity, and cancer (25). In this case, fluorescein diphosphate (FDP) was used as the fluorogenic substrate.…”

Journey to the Center of the Mitochondria Guided by the Tail Anchor of Protein Tyrosine Phosphatase 1B

“…The founding member of its family, protein tyrosine phosphatase 1B (PTP1B) 1,2 (the protein product of the gene PTPN1 3 ) is an important regulator of phosphotyrosine signaling in mammalian cells through its dephosphorylation of a range of substrates 4 , including the receptors for insulin, leptin, and epidermal growth factor (EGF) and their downstream substrates; the tyrosine kinases JAK2 and c-Src; and the tyrosine phosphatase SHP2. PTP1B expression has been detected in several tissues in different mammals 5 and has been proposed as an important inhibitory target for treatment of diabetes, obesity, and cancer 6 .…”

“…How these different pathways might act on PTP1B as well as how these pathways are generally tailored to engage the wide spectrum of tail-anchor-containing proteins remains largely unknown. Post-translational modification of PTP1B in an activating or inhibitory manner occurs by several mechanisms 4 , including phosphorylation (on multiple serines and tyrosines), oxidation, sumoylation, and proteolysis (calpain cleavage).…”